DESCRIPTION: (Applicant's Abstract) Despite increasing interest and investigation devoted to understanding the relationship between cocaine use and cardiovascular disease, there remain considerable voids in our understanding of the mechanisms whereby cocaine impacts on the cardiovascular system. Among the reasons for the slow progress is the lack of appropriate models suitable for chronic study which are both relevant to the human condition, yet allow for experimental manipulations which cannot be performed in humans for both technical and ethical reasons. With support from NIDA, prior studies from this laboratory employing conscious, chronically instrumented dogs, have demonstrated new findings which have challenged previous notions as to the mechanisms and effects of acute cocaine administration on both the coronary circulation and myocardial function, serving to underscore both the relevance of and the need for studies in larger animals in the conscious state. We hypothesize that the effects of chronic cocaine exposure are not merely the sum of its acute effects over time, but rather reflect dynamic alterations in signal transduction pathways which vary with both duration and intensity of exposure and with the component of the cardiovascular system studied (e.g. coronary vascular versus myocardial effects). Specifically, we will characterize and contrast the effects of chronic cocaine exposure compared to acute exposure on the systemic and the coronary circulations. Secondly, we will characterize the effects of chronic cocaine exposure on coronary flow and vasodilator reserve, as potential mechanisms whereby cocaine might predispose to ischemia in the absence of obstructive coronary artery disease. Thirdly, we will determine if the altered coronary vascular responsiveness to binge cocaine use is perpetuated following chronic use and the extent to which altered adrenergic and non adrenergic (nitric oxide) mechanisms contribute to the impairment. Furthermore, we will determine if there is coronary vascular sensitization to adrenergic and non adrenergic vasoconstrictor substances and the role of functionally impaired endothelial responses following chronic daily binge exposure as well as the extent to which these abnormalities are reversible upon cessation of chronic cocaine use. Finally, we will examine the effects of chronic cocaine use not as a trigger to ischemic events, but as a potentiator of the adverse consequences when superimposed against a backdrop of acute myocardial ischemia or impaired myocardial contractile dysfunction. Taken together, these proposed studies will yield new insights into the pathophysiological mechanisms whereby chronic cocaine use predisposes to ischemic insults through alterations in coronary vascular responses.